Published online Sep 15, 2020. doi: 10.4251/wjgo.v12.i9.942
Peer-review started: March 21, 2020
First decision: April 26, 2020
Revised: May 11, 2020
Accepted: July 19, 2020
Article in press: July 19, 2020
Published online: September 15, 2020
Processing time: 172 Days and 20.8 Hours
5-flurouracil (5-FU)-based chemotherapy is the main pharmacological therapy for advanced colorectal cancer (CRC). Despite significant progress in the treatment of CRC during the last decades, 5-FU drug resistance remains the most important cause of failure in CRC therapy. Resistance to 5-FU is a complex and multistep process. Different mechanisms including microsatellite instability, increased expression level of key enzyme thymidylate synthase and its polymorphism, increased level of 5-FU-activating enzymes and mutation of TP53 are proposed as the main determinants of resistance to 5-FU in CRC cells. Recently, micro-ribonucleic acids (miRNA) and their alterations were found to have a crucial role in 5-FU resistance. In this regard, the miRNA-mediated mechanisms of 5-FU drug resistance reside among the new fields of pharmacogenetics of CRC drug response that has not been completely discovered. Identification of the biological markers that are related to response to 5-FU-based chemotherapy is an emerging field of precision medicine. This approach will have an important role in defining those patients who are most likely to benefit from 5-FU-based chemotherapy in the future. Thereby, the identification of 5-FU drug resistance mechanisms is an essential step to predict and eventually overcome resistance. In the present comprehensive review, we will summarize the latest knowledge regarding the molecular determinants of response to 5-FU-based chemotherapy in CRC by emphasizing the role of miRNAs.
Core Tip: Resistance to the main chemotherapy drug, 5-flurouracil (5-FU), is an important cause of failure in clinical colorectal cancer therapy. Microsatellite instability, increased activity and expression level of thymidylate synthase and dihydropyridine dehydrogenase, mutation of TP53 as well as micro-ribonucleic acids alterations are among the main molecular determinants of response to 5-FU-based chemotherapy in colorectal cancer. The identification of potential molecular determinants of response to 5-FU could be an important clinical tool for developing treatment strategies and selecting colorectal cancer patients who are most likely to benefit from 5-FU chemotherapy.